Continuous synthesis of upconverting nanoparticles

ABSTRACT

Synthesizing upconverting nanoparticles includes heating a precursor solution comprising one or more rare earth salts, an alkali metal salt or alkaline earth salt, and a solvent comprising a plasticizer in a microwave reactor to yield a product mixture, and cooling the product mixture to yield the upconverting nanoparticles. Core-shell upconverting nanoparticles are synthesized by combining the upconverting nanoparticles with a precursor solution comprising one or more rare earth salts, an alkali metal salt or alkaline earth salt, and a solvent comprising a plasticizer to yield a nanoparticle mixture, heating the nanoparticle mixture in a microwave reactor to yield a product mixture, and cooling the product mixture to yield the core-shell upconverting nanoparticles.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Patent Application No.63/013,857 entitled “CONTINUOUS SYNTHESIS OF UPCONVERTING NANOPARTICLES”and filed on Apr. 22, 2020, which is incorporated herein by reference inits entirety.

TECHNICAL FIELD

This invention relates to continuous synthesis of upconvertingnanoparticles in a fluidly coupled series of microwave reactors.

BACKGROUND

Upconverting nanoparticles (UCNPs) are nanoparticles that absorb two ormore photons of relatively low energy (e.g., 800 nm to 1000 nm) and emita single photon with higher energy (e.g., 350 nm to 800 nm). In thisupconversion process, there is a large anti-Stokes shift betweenexcitation and emission. The emission bands are narrow, and there is nooverlap between the excitation and emission bands. UCNPs can be used formultimodal optical-electron microscopy or magnetic resonance imaging.These particles typically do not photobleach, even at high excitationpower and duration, and can be excited by relatively low-power,continuous-wave infrared lasers. Since infrared excitation is notphotodamaging, does not excite background fluorescence, and has a deeperpenetration in tissues than UV or visible excitation, thesenanoparticles can be used for live animal and cell imaging, archivedtissue imaging, and intraoperative imaging.

SUMMARY

Methods described in this disclosure allow fabrication of upconvertingnanoparticles (UCNPs) in a scalable, continuous flow fashion using amicrowave reactor using moderately polar, high boiling point solvent(e.g., plasticizers mixed with oleic acid). These methods demonstrate anincrease in production output over current methods by at least a factorof twenty, thereby making UCNPs more suitable for imaging applications(e.g., intraoperative imaging during surgery of tumors).

In a first general aspect, synthesizing upconverting nanoparticlesincludes heating a precursor solution comprising one or more rare earthsalts, an alkali metal salt or an alkaline earth salt, and a solvent ina microwave reactor to yield a product mixture; and cooling the productmixture to yield the upconverting nanoparticles. The solvent comprises aplasticizer including one or both of dioctyl terephthalate andbis(2-ethylhexyl) adipate.

Implementations of the first general aspect may include one or more ofthe following features.

At least one of the one or more rare earth salts comprisestrifluoroacetate. One or more of the rare earth salts comprise one ormore of yttrium, ytterbium, and erbium. The solvent further comprisesoleic acid.

A boiling point of the plasticizer at atmospheric pressure is at least320° C. A dielectric permittivity of the plasticizer is at least 4 or atleast 5. The plasticizer may further include dibutyl phthalate.

The first general aspect may include heating the precursor solution to atemperature of at least 280° C. or at least 305° C. Heating the productmixture can include heating for a length of time between 5 minutes and45 minutes.

Some implementations of the first general aspect include flowing theprecursor solution through the microwave reactor.

In a second general aspect, synthesizing core-shell upconvertingnanoparticles includes heating a precursor solution comprising one ormore rare earth metal salts, an alkali metal salt or an alkaline earthmetal salt, and a solvent in a microwave reactor; combining theupconverting nanoparticles of the first general aspect with theprecursor solution to yield a nanoparticle mixture; heating thenanoparticle mixture to yield a product mixture; and cooling the productmixture to yield the core-shell upconverting nanoparticles. The solventcomprises a plasticizer including one or both of dioctyl terephthalateand bis(2-ethylhexyl) adipate.

Implementations of the second general aspect may include one or more ofthe following features.

The upconverting nanoparticles can have a cubic crystal structure or ahexagonal crystal structure. A boiling point of the plasticizer atatmospheric pressure is at least 320° C. A dielectric permittivity ofthe plasticizer is at least 4 or at least 5. The plasticizer may furtherinclude dibutyl phthalate.

The second general aspect may include heating the precursor solution toa temperature of at least 280° C. or at least 305° C.

Some implementations of the second general aspect include flowing theprecursor solution through the microwave reactor.

The details of one or more embodiments of the subject matter of thisdisclosure are set forth in the accompanying drawings and thedescription. Other features, aspects, and advantages of the subjectmatter will become apparent from the description, the drawings, and theclaims.

BRIEF DESCRIPTION OF DRAWINGS

FIGS. 1A and 1B are schematic representations of microwave flow reactorconfigurations for upconverting nanoparticle (UCNP) synthesis. FIG. 1Adepicts a batch apparatus, and FIG. 1B depicts a continuous flowapparatus.

FIG. 2 shows a typical power and temperature vs. time plot using acommercial microwave reactor for making nanoparticles.

FIG. 3 is a transmission electron microscopy (TEM) image ofNaYF_(4:)ER_(0.02,) Yb_(0.2) UCNPs synthesized by heating to 300° C. for5 minutes.

FIG. 4 shows typical luminescence for NaYF_(4:)Er_(0.02,) Yb_(0.2)excited with a 980 nm laser.

FIG. 5 shows X-ray diffraction patterns of UCNPs as a function ofsolvent composition.

FIG. 6 is a TEM image of UCNPs having a cubic crystal system.

DETAILED DESCRIPTION

The ability to govern the nucleation and growth processes in liquidmedia can be a key to controlling the features of nanoparticles.Solvothermal synthesis of upconverting nanoparticles (UCNPs) involvesthe decomposition of precursors of fluoride and lanthanide ions at hightemperature in the presence of a coordinating ligand and a high boilingpoint solvent medium for decomposition reaction to occur. A fine controlof the reaction temperature can aid in obtaining UCNPs that arehomogeneous both in size and crystalline structure. A high degree ofmonodispersity can require a high rate of nucleation leading to burstnucleation that precludes further nucleation during nanoparticle growth.The cubic (α) to hexagonal ((β) transformation requires prolongedheating for completion.

Conventional heating depends on convection currents and the thermalconductivity from the heating device to the medium. A gradualtemperature increase can affect nucleation and produce broadernanoparticle size distributions. It can also yield a mixture ofparticles with cubic and hexagonal crystalline phases, since thereaction time is measured only once the internal temperature isstabilized. On the other hand, using microwave-assisted synthesis, thereaction can be brought up from room temperature to 300° C. in minutes,since heat can be rapidly and uniformly generated within a certain depthof the reaction mixture, depending on the ability of the reactionmixture components to absorb microwave radiation.

This disclosure describes synthesis of UCNPs by preparing a precursorsolution, heating the precursor solution in one or more heating phasesto nucleate and grow the UCNPs, and quenching the reaction. The UCNPscan be prepared in 15-150 minutes reactor time in a one-pot synthesismethod. Due at least in part to fast and homogeneous microwave heating,it is possible to obtain a narrow size distribution of 10 nm to 20 nm.The nanoparticles can form stable colloidal dispersions (e.g., inisopropanol) at concentrations as high as 2 mg/mL.

Preparing the precursor solution includes combining a solvent andprecursor salts in stoichiometric amounts to yield a mixture. Themixture is heated while stirring under alternating inert gas and vacuumto remove residual air and water to yield the precursor solution. Theprecursor solution is rapidly heated to a temperature above 280° C. in amicrowave reactor. Heating the mixture can include two or moreintermediate heating phases (e.g., typically at 110° C., 220° C., or upto 280° C. for cubic-phase crystalline particles, or 305° C. forhexagonal phase crystalline particles). Each heating phase can rangefrom about 5 minutes to about 30 minutes in length. After nanoparticlenucleation and growth, the reaction is quenched by cooling the mixturewith compressed air to room temperature (e.g., with a minimum averagecooling rate of 20° C/min) to yield UCNPs.

Suitable precursor salts include acetate and trifluoroacetate salts ofalkali metals, alkali rare earth metals, and rare earth elements (Sc, Y,and lanthanides). The precursor salts amounts are calculatedstoichiometrically for a final combined rare earth concentration between1 to 30 millimolar, such that the resulting nanoparticles include acrystalline matrix of a fluoride, for example, NaYF_(4,) NaGdF_(4,)KGdF_(4,) LiYF₄, YbF₃ or YF₃, doped with lanthanides (i.e., partiallyreplacing the Y or Gd ion from 0.1 to 100% with one or more lanthanideions), typically, Er/Yb, Tm/Yb, or Tb/Yb (e.g., NaYF₄).

The solvent is typically an organic solvent. Suitable solvents include amixture of oleic acid and a high boiling point (e.g., 320° C. orgreater), high dielectric permittivity (e.g., at least 4) plasticizer(e.g., dibutyl phthalate, dioctyl terephthalate, bis(2-ethylhexyl)adipate). Other high boiling point plasticizer esters with a dielectricpermittivity larger than 4 are also suitable. The high boiling point,good chemical stability at high temperature, and moderately polarcharacter makes di-n-butyl-phthalate well suited for microwavesynthesis. Oleic acid is used as a ligand to control the size and shapeof the nanoparticles. Non-coordinating solvent 1-octadecene is a verylow-microwave absorber and thus not ideal for this application. Table 1lists boiling point and dielectric permittivity (ε) of various solvents.

TABLE 1 Solvent properties Solvent Boiling Point (° C.) ∈ 1-octadecene315 2.1 oleic acid 350 2.46 di-n-butyl-phthalate 340 6.43

Core-shell nanoparticles can be synthesized by mixing a suspension ofcubic or hexagonal core nanoparticles (e.g. NaYF₄ Er, Yb) with aprecursor solution (e.g., a precursor made with acetate andtrifluoroacetate salts of sodium and ytterbium in stoichiometric ratiosto yield NaYbF₄) to yield a mixture, and heating the mixture in amicrowave reactor with a program similar to that used to obtain coreupconversion nanoparticles to yield, for example NaYF₄:Er, Yb@ NaYbF₄(core @ shell) nanoparticles.

FIGS. 1A and 1B depict microwave flow reactor configurations for UPNPsynthesis. FIG. 1A depicts a batch apparatus 100 for UPNP synthesis.Apparatus 100 includes reaction vessel 102 positioned in microwavereactor 104 for receiving the precursor solution. As depicted, reactionvessel 102 is a round bottom flask. However, reaction vessels of othersizes and shapes can be used. Apparatus 100 includes stirrer 106,temperature sensor 108, and microwave power control feedback 110.Opening 112 in reaction vessel 102 provides access for flow of an inertgas (e.g., argon) and evacuation inside the reaction vessel. The flow ofgas and evacuation can be alternated.

FIG. 1B depicts continuous flow apparatus 120 for synthesis of UPNPs bycontinuously flowing a precursor solution through the apparatus.Reaction vessel 122 is depicted as a spiral borosilicate glass tubepositioned in microwave reactor 124. However, reaction vessels of othersizes and shapes can be used. A precursor solution is provided to inlet126, and a nanoparticle suspension leaves reaction vessel 122 throughoutlet 126′. Continuous flow apparatus 120 includes temperature sensor128 and microwave power control feedback 130. In one example, a particleyield of 30 mg UCNPs per minute can be obtained in an apparatus having areaction vessel with a volume per coil of 50 mL, 3 coil turns, aprecursor flow rate of 15 mL/minute, a residency time of 10 minutes, anda particle concentration of 2 mg/mL.

In many microwave reactors the sample usually is irradiated at one pointrather than over the whole sample volume. Because different materialsabsorb microwaves differently, efficient mixing and fast-respondingtemperature control is advantageous. Reactor flow, such as that providedby the apparatus depicted in FIG. 1B, allows efficient mixing on amacro- or microfluidic scale.

The heating rate in a microwave reactor correlates with the complexdielectric permittivity of the reaction components. The microwaveabsorption cross-section and penetration depth depend on the real partof the dielectric permittivity ε′, while heating due to the dielectricloss through dissipative phenomena is represented by the imaginary partof the dielectric permittivity ε″.

As described herein, a mixture of high boiling point polycarboxylic acidesters and oleic acid (OA) is used in the formation UCNPs.Polycarboxylic acid esters (e.g., bis(2-ethylhexyl) adipate (BEHA),di-n-butyl phthalate (DBP), and di-iso-octyl terephthalate (DOTP)) actas solvents with high boiling points and temperature stability. They aresoluble in most organic solvents, and have adequate polar and microwaveabsorbing characteristics.

In some implementations, a continuous flow apparatus includes one ormore (e.g., three) fluidly coupled microwave reactors configured suchthat the precursor solution flows sequentially through each reactor toyield UCNPs.

FIG. 2 shows a typical power and temperature vs. time plot using acommercial microwave reactor for making UCNPs. For the plot in FIG. 2,the precursor solution was heated for 5 minutes to 300° C.

FIG. 3 shows a transmission electron microscopy (TEM) image ofNaYF_(4:)ER_(0.02,) Yb_(0.2) UCNPs synthesized by heating a precursorsolution to 300° C. for 5 minutes.

FIG. 4 shows typical luminescence for NaYF_(4:)Er0.02, Yb_(0.2) excitedwith a 980 nm laser.

EXAMPLES

Example 1. Trifluoroacetate (TFA) salts of sodium, yttrium, ytterbium,and erbium were dissolved in a mix of oleic acid and di-butyl-phthalateat different ratios by first heating the solution at 120° C. for 10minutes, followed by heating at 315° C. for 10 to 120 minutes.Trifluoroacetate salts and di-n-butyl phthalate are good microwaveabsorbers and allow the temperature to rise from 120° C. to 315° C. inapproximately 5 minutes. The microwave reactor was a CEM Discover usingsingle mode and continuous power at 2.45 GHz.

Colloidal nanoparticle dispersions in 2-propanol at 5 mg/ml were excitedwith a 500 mW, 980 nm laser. The lifetimes of the green (540 nm) and thered (655 nm) emission were obtained by exciting the samples with 10 mslaser pulses. The emitted light was focused on a Jobin-Yvon HRspectrometer, and detected using a photomultiplier and an averageroscilloscope. The lifetime of these nanoparticles ranges from 200 to 150μs at 540 nm, and from 320 to 250 μs at 655 nm, and follows a decreasingtrend with increasing synthesis time.

Example 2. A single mode 2.45 GHz microwave reactor (Discover, CEM,Matthews NC, USA) equipped with a high temperature PTFE-spill cup and animmersion optical fiber thermometer supplied by its manufacturer wasused. All pure solvents were degassed under vacuum and magnetic stirringat room temperature for at least 30 minutes prior to being used. A stockrare-earth precursor solution was prepared in advance and stored up totwo months before use. Briefly, a 100 mM total rare earth concentrationsolution was prepared in advance and stored. 20 mL of oleic acid wasdegassed under vacuum and stirred for at least 30 minutes in a roundbottom flask. Reagents were mixed in stoichiometric proportions toobtain NaY_(0.78)F_(4:)Yb_(0.2), Er_(0.02). Briefly, 773.05 mg YTFA(TFA=trifluoroacetate), 151.98 mg YbAc (Ac=acetate), 14.99 mg ErAc,205.2 mg NaTFA, and 125.19 mg NaAc were added to the flask. The mixturewas heated to 100° C. in a microwave reactor under argon flow andstirred for 10 minutes. The stock precursor solution was stored at roomtemperature for a minimum of 45 minutes before using it, and up to twomonths.

An aliquot of the nanoparticle precursor stock solution was combinedwith an oleic acid (OA): bis(2-ethylhexyl) adipate (BEHA) mixture atdifferent proportions (S1 to S6, see Table 2) into a 125 mL round-bottomflask. The flask was placed in a microwave cavity and kept under agentle argon flow and stirring using a glass-coated magnet for 10minutes, and then heated to 300° C. for 5-45 minutes. At the end of theheating program the flask was cooled down to room temperature by astream of compressed air.

TABLE 2 Synthesis parameters Sample OA (% v/v) BEHA (% v/v) S1 80.0 20.0S2 65.0 35.0 S3 50.0 50.0 S4 35.0 65.0 S5 16.7 83.3 S6 8.4 91.7

Scaled-up continuous flow synthesis: The mixture of the nanoparticlestock precursor solution with oleic acid and a carboxylic acid ester wasflowed through microwave reactor coils to heat it to a temperature above280° C. with a residence time from 5 to 45 minutes.

FIG. 5 shows X-ray diffraction patterns of the resulting UCNPs as afunction of the OA-BEHA ratio. Sample Si was consistent with sodiumerbium ytterbium yttrium fluoride (reference code 04-022-6704) with anempirical formula of Er_(0.01)FY₂Na_(0.5)Y_(0.39)Yb_(0.1) and having acubic crystal structure. Sample S6 was seen to be consistent with sodiumerbium ytterbium yttrium fluoride (reference code 00-028-1192) with anempirical formula of Er0.04F₄NaY_(0.57)Yb_(0.39) (chemical formulaNa(Y_(0.57)Yb_(0.39)Er_(0.04))F₄ and having a hexagonal crystalstructure. FIG. 5 is a transmission electron microscopy image of SampleS5, prepared with a microwave residence time of 15 minutes at 300° C.The nanoparticles have a hexagonal crystalline structure, and diametersranging from about 40 nm to about 130 nm, with a majority of thenanoparticles having a diameter of about 100 nm.

Although this disclosure contains many specific embodiment details,these should not be construed as limitations on the scope of the subjectmatter or on the scope of what may be claimed, but rather asdescriptions of features that may be specific to particular embodiments.Certain features that are described in this disclosure in the context ofseparate embodiments can also be implemented, in combination, in asingle embodiment. Conversely, various features that are described inthe context of a single embodiment can also be implemented in multipleembodiments, separately, or in any suitable sub-combination. Moreover,although previously described features may be described as acting incertain combinations and even initially claimed as such, one or morefeatures from a claimed combination can, in some cases, be excised fromthe combination, and the claimed combination may be directed to asub-combination or variation of a sub-combination.

Particular embodiments of the subject matter have been described. Otherembodiments, alterations, and permutations of the described embodimentsare within the scope of the following claims as will be apparent tothose skilled in the art. While operations are depicted in the drawingsor claims in a particular order, this should not be understood asrequiring that such operations be performed in the particular ordershown or in sequential order, or that all illustrated operations beperformed (some operations may be considered optional), to achievedesirable results.

Accordingly, the previously described example embodiments do not defineor constrain this disclosure. Other changes, substitutions, andalterations are also possible without departing from the spirit andscope of this disclosure.

What is claimed is:
 1. A method of synthesizing upconvertingnanoparticles, the method comprising: heating a precursor solutioncomprising one or more rare earth salts, an alkali metal salt or analkaline earth salt, and a solvent in a microwave reactor to yield aproduct mixture; and cooling the product mixture to yield theupconverting nanoparticles, wherein the solvent comprises a plasticizerincluding one or both of dioctyl terephthalate and bis(2-ethylhexyl)adipate.
 2. The method of claim 1, wherein at least one of the one ormore rare earth salts comprises trifluoroacetate.
 3. The method of claim1, wherein the one or more rare earth salts comprise one or more ofyttrium, ytterbium, and erbium.
 4. The method of claim 1, wherein thesolvent further comprises oleic acid.
 5. The method of claim 1, whereina boiling point of the plasticizer at atmospheric pressure is at least320° C.
 6. The method of claim 1, wherein a dielectric permittivity ofthe plasticizer is at least 4 or at least
 5. 7. The method of claim 1,wherein the plasticizer further comprises dibutyl phthalate.
 8. Themethod of claim 1, comprising heating the precursor solution to atemperature of at least 280° C.
 9. The method of claim 8, comprisingheating the precursor solution to a temperature of at least 305° C. 10.The method of claim 1, wherein heating the product mixture comprisesheating for a length of time between 5 minutes and 45 minutes.
 11. Themethod of claim 1, further comprising flowing the precursor solutionthrough the microwave reactor.
 12. A method of synthesizing core-shellupconverting nanoparticles, the method comprising: heating a precursorsolution comprising one or more rare earth metal salts, an alkali metalsalt or an alkaline earth metal salt, and a solvent in a microwavereactor; combining the upconverting nanoparticles of claim 1 with theprecursor solution to yield a nanoparticle mixture; heating thenanoparticle mixture to yield a product mixture; and cooling the productmixture to yield the core-shell upconverting nanoparticles, wherein thesolvent comprises a plasticizer including one or both of dioctylterephthalate and bis(2-ethylhexyl) adipate.
 13. The method of claim 12,wherein the upconverting nanoparticles comprise cubic nanoparticles. 14.The method of claim 12, wherein the upconverting nanoparticles comprisehexagonal nanoparticles.
 15. The method of claim 12, wherein a boilingpoint of the plasticizer at atmospheric pressure is at least 320° C. 16.The method of claim 12, wherein a dielectric permittivity of theplasticizer is at least 4 or at least
 5. 17. The method of claim 12,wherein the plasticizer further comprises dibutyl phthalate.
 18. Themethod of claim 12, comprising heating the precursor solution to atemperature of at least 280° C.
 19. The method of claim 18, comprisingheating the precursor solution to a temperature of at least 305° C. 20.The method of claim 12, further comprising flowing the precursorsolution through the microwave reactor.